Institute of Molecular Medicine
This article first appeared in MRC News, Winter 1996, and is reproduced here with the permission of MRC and Professor Andrew McMichael. Free copies of MRC News and other publications describing MRC research activities are available from:
© MRC 1996.
We still do not fully understand how some viruses persist and cause chronic disease, including cancer. For instance, while we know that AIDS results from the HIV virus overcoming part of the immune system, we don't know exactly how it does this, while avoiding being destroyed itself. But we do know that the relationship between the infecting virus and the immune system is central to the story. If we could find out why the immune response fails to see off invaders such as HIV, we should be able to develop more effective treatments. Work in my laboratory at Oxford, supported by the MRC, is focusing on one key player: a type of immune or white blood cell known as the cytotoxic or 'killer' T-cell.
When the immune system encounters a virus for the first time, every component of the system goes on red alert. At first, as viruses infect susceptible cells, they multiply unconstrained by any immune response. But after a variable length of time - four or five days for influenza but two to three weeks for HIV - the first immune response becomes detectable. This is the T-cell response, made up of both 'killer' and 'helper' cells. The killer cells destroy virus-infected cells before they have time to release large quantities of new virus particles. The helper cells secrete special compounds, called cytokines, some of which have antiviral activity - interferon is a well known example. Other cytokines are involved in controlling inflammation, while yet others drive the B-cells of the immune system to make antibodies to help combat the invaders.
In some infections the action of these T-cells is visible to the naked eye: they cause a rash as they promote inflammation around a focus of infected cells in the skin. Measles, for example, appears to get worse as the rash appears but then recovery is rapid. In another example, as the virus which causes hepatitis A multiplies quietly in liver cells, the T cells move into the scene. Killer cells destroy virus-infected cells, but in so doing damage the liver, causing jaundice. But once the patient is through that stage, recovery is usually rapid and complete.
The production of antibodies, which lags behind the T-cell response, may help in recovery but is not essential. Antibodies' real role in life is to prevent further viral attacks. In this they are incredibly successful. For example, it is extremely rare for anyone to have more than one attack of the childhood viral infections such as mumps, measles or chicken pox. Furthermore, pregnant mothers pass on antibodies to their babies, providing protection against infection during their first six months of life. Thus the baby benefits from the mother's previous infections, even if the viral 'challenge' happened more than thirty years earlier! Some viruses, however, can evade anti body immunity by changing their outer coats; the classic example is the rapidly evolving influenza virus which changes its surface coating from year to year. Unlike measles or mumps, humans suffer flu infections every few years throughout life.
|Hepatitis B||Liver Cancer||Yes|
|Epstein Barr virus||Lymphomas, NPC||No|
In our laboratory we have focused on the immune response to HIV in an attempt to understand how the virus escapes from control by killer cells - this is probably one important reason why it can go on to cause AIDS. As in other viral infections, the initial burst of viral proliferation is at first brought under control by the killer T-cell response. Then antibodies against the virus appear which can neutralise some of the released virus particles. For most people with HIV, the infection is kept at bay for some years and the patient feels healthy. We now know, however, that, despite an immune system which is still active, the virus somehow continues to replicate at quite high levels during this period. This results in the infected cells, the helper T-cells and macrophages of the immune system, being slowly but relentlessly destroyed. Eventually the whole immune response fails.
Once a cell has been infected by a virus, enzymes chop up the viral proteins into short strings, or peptides, which are then transported across the cell membrane into a compartment called the endoplasmic reticulum. Here the peptides fit into a groove on the top of molecules of a cell protein called HLA. The HLA molecule and its bound bit of viral peptide then travels to the surface of the infected cell. There, if all goes well, the killer cell spots it, recognises the peptide as foreign and kills the cell. In effect, the infected cell is labelling itself as can non fodder - sacrificing itself for the greater good of the organism as a whole. But the binding of peptide to the HLA molecules, a very precise process, is a vital step in the immune response. If something goes wrong with this process, the immune response can be fatally undermined.
We each possess a unique array of HLA genes, which define and produce molecules that vary in structure from one individual to another. Thanks to our distinctive HLA molecules, each of us reacts to viruses in a distinctive way: our HLA molecules react to and bind different peptides from distinct viruses. This may have major consequences for our susceptibility to persistent viruses.
Unfortunately, viruses that are highly variable, like HIV, have found a way to interfere with the binding process. In particular, small genetic changes in the virus - mutations - alter the structure of the virus peptide, destroying the 'fit' between it and the HLA molecules. As a result, the altered peptide may no longer stimulate an immune response, and so may be able to persist in the body undetected by killer T cells. Often the mutated peptide still binds with HLA but the combined shape is so altered that the killer cell simply does not recognise it. Sometimes the mutated duo no longer fit into the appropriate docking molecule or receptor on the T cell. Alternatively, the mutated peptide may dock only half-heartedly, so that the receptor delivers a weakened signal to the T cell, effectively putting the T-cell out of action:
The key question is: why can't killer T-cells control or eliminate this virus? Clues come from other persisting viruses; it is becoming clear that these viruses have evolved strategies to evade killer cells. Epstein Barr virus, for instance, causes glandular fever but then persists harmlessly in more than 85% of infected individuals. It persists because it stops the cells it infects from generating, fragments of viral proteins, or peptides, that normally signal its presence and stimulate killer cell responses.
As a result of this interference, the virus goes by undetected. Herpes simplex virus, which causes recurrent cold sores, also interferes with the processing of the viral proteins into the immunologically stimulating peptide fragments, but in a different way. Adenoviruses, like the ones which cause colds, make themselves non immunogenic by interrupting the same process in another way. HIV however, does not have to use this kind of strategy: it can probably subvert the killer T-cell response simply by having such a variable molecule.
In the absence of a killer response HIV invades and kills the helper cells and multiplies rapidly so that progression to AIDS is fast. When the killer cells are able to recognise and kill HIV infected cells, the virus is controlled but only at cost: for inevitably, the helper cells infected with HIV are also killed. Sadly, the maintenance of the killer response depends on the helper cells, so the killer cells eventually cut off their own lifeline:
This may be one reason why killer cells eventually fail to control HIV. The rate of this failure depends on various factors including the intrinsic aggression of the infecting strain of HIV, the overall health of the individual, their ability to replenish stocks of helper cells and the vigour of the killer cell response. The strength of the killer cells in turn depends largely on ever-mutating virus. If by good fortune an individual's HLA molecules zero in on the less variable, 'conserved' parts of the virus, the killer cell response will be more stable. The specificity of the killer response is itself determined by the HLA molecules, and ultimately, by the HLA genes an individual happens to possess.
This brief summary of HIV immunity illustrates another point about killer T-cells: they can sometimes contribute to disease. Some viruses infect cells but do not cause them much damage and do not themselves kill the cell, at least in the short term.
A good example is hepatitis B virus. If a killer response is stimulated, the T cells kill the infected liver cells, damaging the liver. If in doing so they eliminate the virus, this may be a price worth paying, but sometimes they can cause more damage than the virus ever would. But although hepatitis B virus may itself cause little direct damage, the infection is strongly associated with liver cancer - one of the world's commonest cancers, and so total elimination of the virus is desirable in the long term.
An understanding of the killer response and its role in immunity is beginning to lead to better vaccines and new kinds of treatment, known as immunotherapy. Traditional vaccines have been aimed at stimulating an effective antibody response against viruses such as influenza, hepatitis B, measles, mumps and polio. Yet researchers have long realised that live virus vaccines - where the virus is attenuated or made less vicious are more effective, probably because they are better at stimulating the T-cell responses. Unfortunately, sometimes it is not feasible or is too dangerous to attenuate a virus - and this is the case with HIV. So researchers in both industrial and academic laboratories are now trying to develop safe and simple vaccines that stimulate strong killer responses. Such vaccines should offer better protection against infection with viruses, including HIV. There is an attenuated version of the monkey variant of HIV, known as SIV, which protects macaques from infection with SIV and the development of AIDS. This work was done by Ron Desrosiers in Boston and in the UK by Jim Stott, Martin Cranage and colleagues funded by the MRC. This research has led some scientists to ask whether an attenuated version of HIV could be developed. The problem is that such a vaccine would infect permanently and might perhaps cause disease in the long run. It would be much better to mimic these immune responses by vaccines with less potential risk.
It would be better if we could control or eliminate established viral infections by directly manipulating the immune responses in infected patients. Redirecting immune responses to the most vulnerable parts of a virus-such as the conserved regions of HIV might be an effective approach. Altering immune responses to a variety of infections by injecting antibodies, cytokines or even cells is also under investigation. One of the most encouraging examples is the remission of a cancer linked to Epstein-Barr virus, called EBV associated lymphoma, in people receiving bone marrow transplants, whose immune systems are suppressed. Their cancers receded after they were given infusions of EBV-specific killer cells grown in culture. It might also be possible to modify such cells by gene therapy before treatment.
The killer T-cell response is a key part of the immune response to a viral infection, complementing the antibody response. Killer cells are usually good at inhibiting the infection, but they may fail, allowing the virus to persist. Unravelling how and why this happens is central to a better understanding of viral infections. Furthermore, developing vaccines that stimulate killer cells is an important priority for many viruses where vaccines are either not available or unsatisfactory.
Professor Andrew McMichael is a MRC Clinical Research Professor of Immunology and heads the Molecular Immunology Group at the Institute of Molecular Medicine in Oxford. His research focuses on the immune response to virus infections, in particular HIV. He is a member of the MRC's Molecular and Cell Medicine Board, and also sits on the AIDS Research Coordinating Committee.
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